The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis. New insights into the associated signaling pathways.
Strontium ranelate exerts both an anti-catabolic and an anabolic effect on bone cells. To further investigate the molecular mechanism whereby strontium ranelate inhibits bone resorption, we focused our attention on the effects of strontium ranelate on osteoclast apoptosis and on the underlying mechanism(s). Using primary mature rabbit osteoclasts, we demonstrated that strontium (Sro2+) dose-dependently stimulates the apoptosis of mature osteoclasts. As shown previously for calcium (Cao2+), the Sro2+-induced effect on mature osteoclasts is mediated by the Cao2+-sensing receptor, CaR, which in turn stimulates a phospholipase C-dependent signaling pathway and nuclear translocation of NF-kappaB. Unlike Cao2+, however, Sro2+-induced osteoclast apoptosis was shown to depend on PKCbetaII activation and to be independent of inositol 1,4,5-trisphosphate action. As a consequence of these differences in their intracellular signaling pathways, Sro2+ and Cao2+ in combination were shown to exert a greater effect on mature osteoclast apoptosis than did either divalent cation by itself. Altogether, our results show that Sro2+ acts through the CaR and induces osteoclast apoptosis through a signaling pathway similar to but different in certain respects from that of Cao2+. This difference in the respective signaling cascades enables Sro2+ to potentiate Cao2+-induced osteoclast apoptosis and vice versa. In this manner, it is conceivable that Sro2+ and Cao2+ act together to inhibit bone resorption in strontium ranelate-treated patients.
Hurtel-Lemaire
Anne S
AS
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Mentaverri
Romuald
R
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Caudrillier
Axelle
A
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Cournarie
Fabienne
F
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Wattel
Alice
A
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Kamel
Said
S
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Terwilliger
Ernest F
EF
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Brown
Edward M
EM
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Brazier
Michel
M
INSERM ERI-12, 1 rue des Louvels, 80037 Amiens, France, Institut de Recherches Internationales Servier, 6 place des Pláiades, 92415 Courbevoie, France, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: michel.brazier@sa.u-picardie.fr.
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D011817:Rabbits; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism
D050071:Bone Density Conservation Agents; D016328:NF-kappa B; D009942:Organometallic Compounds; D044169:Receptors, Calcium-Sensing; D013876:Thiophenes; C081587:strontium ranelate; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D010738:Type C Phospholipases; D002118:Calcium